Non-invasive Ultrasonic Tissue Fractionation for Treatment of Benign Disease and Cancer -“Histotripsy”
Ultrasound has been widely known for diagnostic imaging. Recent studies suggest that it also has potential to be developed as a non-invasive therapy tool. Ultrasound has the ability to focus energy deep within the human body without damaging the overlying tissue. If the energy is sufficient, significant bioeffects (e.g., tissue necrosis and tissue fractionation) can be achieved. This ability of ultrasound is suited perfectly for many types of non-invasive therapy.
Our lab invented a non-invasive mechanical ultrasound therapy technology, which we termed “histotripsy” in 2003 and published the first paper on histotripsy in 2004 . “Histo” means soft tissue in Greek, and “tripsy” means breakdown. Using microsecond-length focused ultrasound pulses applied from outside the body, micro bubbles are generated from endogenous nanometer gas pockets in the target tissue [2,3]. When the ultrasound pressure exceeds the cavitation threshold, the nanometer gas pockets rapidly expand to ~100 microns followed by the collapse in hundreds of microseconds — a process that produces high strain to disrupt cells within the target volume into a liquid-appearing acellular debris . Histology demonstrates treated tissue within the lesion is fragmented to subcelluar level surrounded by an almost imperceptibly narrow margin of cellular injury  (Fig. 1A). Histotripsy-induced cavitation and tissue homogenization can be clearly visualized and imaged by diagnostic ultrasound imaging (Fig. 1B).
Fig. 1: A) Histology of the porcine heart tissue treated by histotripsy, showing a very sharp boundary with individual bisected cells. B) Ultrasound image of a M-shaped lesion generated by histotripsy in the porcine liver tissue.
Histotripsy uses acoustic cavitation to mechanically disrupt the target tissue and is entirely different from high intensity focused ultrasound (HIFU) thermal therapy that uses ultrasound to heat the target tissue. Histotripsy uses microsecond ultrasound pulses at a low duty cycle (ultrasound on-time/total treatment time <1%), whereas HIFU uses continuous ultrasound or second-length ultrasound pulses at a high duty cycle (>20%). Histotripsy is not impacted by the heat sink effect and thus has the potential to overcome many of the limitations associated with thermal ablation.
As a platform non-invasive therapy, histotripsy has many applications. Our lab has studied histotripsy in preclinical studies for treating cancer [6-8], cardiac diseases [9,10], thrombosis [11,12], = neurological applications [13-15]. In addition, we have shown that histotripsy local tumor ablation stimulates significant immune response [16-18], reduced metastasis , and extended survival [6,7]. Our work has led to completed Phase I clinical trials using histotripsy for treatment of benign prostatic hyperplasia19 (NCT01896973) and liver cancer [20,21] (NCT03741088), and multi-center histotripsy clinical trials on liver cancer (Hope4Liver) are ongoing in the U.S. (NCT04572633) and Europe (NCT04573881).
University Innovator Award -August 8th, – Distinguished University Innovator Award
Mar 30, 2023 – HistoSonics Announces First Ever Kidney Tumor Treatment Using
Mar 16, 2023 – International Society of Therapeutic Ultrasound (ISTU) Webinar by Zhen
Xu: Histotripsy Cancer Treatment: The Road to Bench to Bedside – link
Jan 31, 2023 – How sound waves trigger immune responses to cancer in mice – link
Jun 7, 2022 – 21st Annual International Symposium on Therapeutic Ultrasound (ISTU)
keynote speaker Zhen Xu https://istu.org/istu-2022-toronto/
April 18, 2022 – Tumors partially destroyed with sound don’t come back – link
March 6, 2022 – Prof. Zhen Xu won 2021-22 College of Engineering Rexford E. Hall
Innovation Excellence Award – http://adaa.engin.umich.edu/wpcontent/uploads/sites/22/2021/09/CoE-Faculty-Award-Recipients-2019-20.pdf
Nov 1, 2021 – 43rd Annual International Conference of the IEEE Engineering in Medicine and
Biology Society (EMBC) keynote speaker Zhen Xu – link
June 4, 2021 – Histotripsy technology used in a clinical trial to treat liver tumors – https://michigan.it.umich.edu/news/2021/06/04/histrotripsy-technology-used-to-treat-livertumors/
March 12, 2020 – University of Michigan Researcher Zhen Xu Receives Lockhart Memorial Prize from Focused Ultrasound Foundation – Link https://www.fusfoundation.org/posts/university-of-michigan-researcher-receives-lockhartmemorial-prize-from-focused-ultrasound-foundation/
March 10, 2020 – Watch Now: Webinar on Histotripsy to Treat Cancer and Neurological Diseases – link Watch Now: Webinar on Histotripsy to Treat Cancer and Neurological Diseases – Focused Ultrasound Foundation (fusfoundation.org)
 Xu, Z., Ludomirsky, A., Eun, L. Y., Hall, T. L., Tran, B. C., Fowlkes, J. B. & Cain, C. A.
Controlled ultrasound tissue erosion. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 51, 726-736, (2004). PMC2669757
 Maxwell, A. D., Wang, T. Y., Cain, C. A., Fowlkes, J. B., Sapozhnikov, O. A., Bailey, M.R. & Xu, Z. Cavitation clouds created by shock scattering from bubbles during histotripsy. The Journal of the Acoustical Society of America 130, 1888-1898, (2011). 3206907
 Maxwell, A. D., Cain, C. A., Hall, T. L., Fowlkes, J. B. & Xu, Z. Probability of cavitation for single ultrasound pulses applied to tissues and tissue-mimicking materials. Ultrasound Med. Biol. 39, 449-465, (2013). 3570716
 Vlaisavljevich, E., Maxwell, A., Mancia, L., Johnsen, E., Cain, C. & Xu, Z. Visualizing the Histotripsy Process: Bubble Cloud-Cancer Cell Interactions in a Tissue-Mimicking Environment. Ultrasound Med Biol 42, 2466-2477, (2016). PMC5010997
 Parsons, J. E., Cain, C. A., Abrams, G. D. & Fowlkes, J. B. Pulsed cavitational ultrasound therapy for controlled tissue homogenization. Ultrasound Med Biol 32, 115- 129, (2006).
 Worlikar, T., Mendiratta-Lala, M., Vlaisavljevich, E., Hubbard, R., Shi, J., Hall, T. L., Cho, C. S., Lee, F. T., Greve, J. & Xu, Z. Effects of Histotripsy on Local Tumor Progression in an in vivo Orthotopic Rodent Liver Tumor Model. BME Frontiers, (2020).
 Worlikar, T., Zhang, M., Ganguly, A., Hall, T. L., Shi, J., Zhao, L., Lee, F. T., Mendiratta- Lala, M., Cho, C. S. & Xu, Z. Impact of Histotripsy on Development of Intrahepatic Metastases in a Rodent Liver Tumor Model. Cancers (Basel) 14, 1612, (2022). PMC8996987
 Styn, N. R., Hall, T. L., Fowlkes, J. B., Cain, C. A. & Roberts, W. W. Histotripsy of renal implanted VX-2 tumor in a rabbit model: investigation of metastases. Urology 80, 724- 729, (2012).
 Owens, G. E., Miller, R. M., Ensing, G., Ives, K., Gordon, D., Ludomirsky, A. & Xu, Z. Therapeutic ultrasound to non-invasively create intracardiac communications in an intact animal model. Catheter Cardiovasc Interv. 77, 580-588, (2011). PMC3010446
 Xu, Z., Owens, G., Gordon, D., Cain, C. A. & Ludomirsky, A. Non-invasive Creation of an Atrial Septal Defect by Histotripsy in a Canine Model. Circulation 121, 742-749, (2010). PMC2834201
 Maxwell, A. D., Owens, G., Gurm, H. S., Ives, K., Myers, D. D., Jr. & Xu, Z. Noninvasive treatment of deep venous thrombosis using pulsed ultrasound cavitation therapy (histotripsy) in a porcine model. Journal of vascular and interventional radiology 22, 369-377, (2011). 3053086
 Zhang, X., Macoskey, J. J., Ives, K., Owens, G. E., Gurm, H. S., Shi, J., Pizzuto, M., Cain, C. A. & Xu, Z. Non-Invasive Thrombolysis Using Microtripsy in a Porcine Deep Vein Thrombosis Model. Ultrasound Med Biol 43, 1378-1390, (2017). PMC5440202
 Lu, N., Gupta, D., Daou, B. J., Fox, A., Choi, D., Sukovich, J. R., Hall, T. L., Camelo- Piragua, S., Chaudhary, N., Snell, J., Pandey, A. S., Noll, D. C. & Xu, Z. Transcranial Magnetic Resonance-Guided Histotripsy for Brain Surgery: Pre-clinical Investigation. Ultrasound Med Biol 48, 98-110, (2022).
 Sukovich, J. R., Cain, C. A., Pandey, A. S., Chaudhary, N., Camelo-Piragua, S., Allen, S. P., Hall, T. L., Snell, J., Xu, Z., Cannata, J. M., Teofilovic, D., Bertolina, J. A., Kassell, N. & Xu, Z. In vivo histotripsy brain treatment. J Neurosurg, 1-8, (2018). PMC6925659
 Gerhardson, T., Sukovich, J. R., Chaudhary, N., Chenevert, T. L., Ives, K., Hall, T. L., Camelo-Piragua, S., Xu, Z. & Pandey, A. S. Histotripsy Clot Liquefaction in a Porcine Intracerebral Hemorrhage Model. Neurosurgery 86, 429-436, (2020). PMC7308653
 Qu, S., Worlikar, T., Felsted, A. E., Ganguly, A., Beems, M. V., Hubbard, R., Pepple, A. L., Kevelin, A. A., Garavaglia, H., Dib, J., Toma, M., Huang, H., Tsung, A., Xu, Z. & Cho, C. S. Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy. J Immunother Cancer 8, (2020). PMC7057529
 Schade, G. R., Wang, Y. N., D’Andrea, S., Hwang, J. H., Liles, W. C. & Khokhlova, T. D. Boiling Histotripsy Ablation of Renal Cell Carcinoma in the Eker Rat Promotes a Systemic Inflammatory Response. Ultrasound Med Biol 45, 137-147, (2019). PMC6546431
 Pepple, A. L., Guy, J. L., McGinnis, R., Felsted, A. E., Song, B., Hubbard, R., Worlikar, T., Garavaglia, H., Dib, J., Chao, H., Boyle, N., Olszewski, M., Xu, Z., Ganguly, A. & Cho, C. S. Spatiotemporal local and abscopal cell death and immune responses to histotripsy focused ultrasound tumor ablation. Front Immunol 14, 1012799, (2023). PMC9900174
 Schuster, T. G., Wei, J. T., Hendlin, K., Jahnke, R. & Roberts, W. W. Histotripsy Treatment of Benign Prostatic Enlargement Using the Vortx Rx System: Initial Human Safety and Efficacy Outcomes. Urology, (2018).
 Vidal-Jove, J., Serres-Creixams, X., Ziemlewicz, T. J. & Cannata, J. M. Liver Histotripsy Mediated Abscopal Effect-Case Report. IEEE Trans Ultrason Ferroelectr Freq Control 68, 3001-3005, (2021).
 Vidal-Jove, J., Serres, X., Vlaisavljevich, E., Cannata, J., Duryea, A., Miller, R., Merino, X., Velat, M., Kam, Y., Bolduan, R., Amaral, J., Hall, T., Xu, Z., Lee, F. T., Jr. & Ziemlewicz, T. J. First-in-man histotripsy of hepatic tumors: the THERESA trial, a feasibility study. Int. J. Hyperthermia 39, 1115-1123, (2022).